Project Summary This application is a competing continuation of an Autism Center of Excellence (ACE) Network grant now entitled, `A Longitudinal Brain and Behavior Study of Autism from Infancy through School Age`. Prior funding has supported a prospective, longitudinal study that has collected high quality brain imaging and behavior assessments in children at high- and low- familial risk (HR, LR) for an autism spectrum disorder (ASD), at 2-4 time points (including 3, 6, 9, 12, 15 and 24 months) with 36 month diagnostic re-assessment for autism. This project has been successful in producing 50 manuscripts either published/in press (#35) or under review (#15); and generated 21 external funding opportunities, leveraging this network and expanding the scope of this work. The overarching goal of this ACE Network competing continuation is to continue to follow a unique cohort of 300 HR and 100 LR children into school age (7-10 years) with detailed brain and behavior assessments. School age is a time when academic and social functioning are critically important for future success and a time when HR children are prone to manifest comorbid psychiatric disorders, difficulties with peer relationships, and learning problems which can be assessed more extensively and with greater detail than at earlier ages. Work from this network has revealed that: (1) early brain imaging features are detectable by 6 months of age, well before ASD diagnosis is possible, in those who go on to have an ASD diagnosis at 24 months; (2) autism-specific brain and behavior features change substantially from 6-24 months of age, as autism unfolds; and, (3) brain features in the first year of life are associated with later ASD behaviors and accurately predict individual ASD diagnosis at 24 months. The proposed work extends this solid foundation. In this proposal we aim to: (1) characterize school- age clinical outcomes of HR children and determine early predictors of those clinical outcomes from brain imaging and behavioral features we have already identified from 3-36 months; (2) characterize brain and brain- behavior trajectories in HR-ASD from infancy through school-age and identify the timing of ASD-related brain changes; and (3) empirically derive and validate novel subgroups within the HR group based on brain and behavior trajectories from infancy through school age, incorporating data from molecular genetics and environmental exposures. The potential impact of this study includes: (1) early identification (< 3 years) of children who are more likely to develop school-age (7-10 years) clinical problems, increasing the potential for early intervention; (2) informing intervention studies by identifying age-specific brain targets, biomarkers of treatment efficacy, and targets for pre-clinical, cross-species studies to inform drug development; and,(3) identifying empirically-derived and biologically-meaningful subgroups, based on brain and behavior trajectories from infancy to school age, that could be used to support development of individualized interventions.